Neuroblastoma is the most common and deadly solid tumor in children, but this tumor also has a very high propensity to undergo spontaneous differentiation or regression. Evidence suggests that the Trk family of neurotrophin receptors play a critical role in tumor behavior. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous differentiation or regression. In contrast, Neuroblastomas expressing TrkB usually have MYCN amplification and are among the most aggressive and deadly tumors known. These tumors usually express P75, but the effect of P75 alone or when co-expressed with TrkA or TrkB in neuroblastomas is unknown. We are exploring the biological role of P75 and Trk proteins in mediating apoptosis, differentiation or survival of neuroblastoma cells, and the therapeutic potential of targeting these signaling pathways in neuroblastomas. Our aims are: Specific Aim 1. Determine if P75-expressing neuroblastoma cells undergo apoptosis in response to ligand. Specific Aim 2. Determine if P75 coexpression alters the response of TrkA or TrkB expressing neuroblastoma cells to ligand. Specific Aim 3. Analyze the consequences of Trk inhibition, alone or in combination with conventional and biological agents, on neuroblastoma xenografts. The successful completion of these studies should lead to a better understanding of the mechanism of apoptotic death mediated by P75, and the important effects P75 co-expression has on Trk function (and vice versa). We will also determine the efficacy of the novel tyrosine kinase inhibitors in treating Trk-expressing tumors in combination with conventional and biological agents. These data should provide compelling evidence for the utility of Trk receptor inhibition therapy in combination with other agents and facilitate the rational inclusion of Trk inhibitors into clinical trials.